Histamine is a chemical messenger involved in various complex biological actions. When released, histamine interacts with specific macromolecular receptors on the cell surface or within a target cell to elicit changes in many different bodily functions. Various cell types including smooth muscle, blood cells, cells of the immune system, endocrine and exocrine cells as well as neurons respond to histamine by stimulating the formation of intracellular signals, including formation of phosphatidylinositol or adenylate cyclase. Evidence that histamine plays a role as a neurotransmitter was established by the mid to late 1970's (Schwartz, 1975) Life Sci. 17: 503-518. Immunohistochemical studies identified histaminergic cell bodies in the tuberomammillary nucleus of the posterior hypothalamus with widespread projections in the dicencephalon and telencephalon (Inagaki et al., 1988) J. Comp. Neurol. 273: 283-300.
Identification of two histamine receptors (H.sub.1 and H.sub.2) was reported to mediate the biochemical actions of histamine on neurons. Recently, studies have demonstrated the existence of a third subtype of histamine receptor, the histamine H.sub.3 receptor (Schwartz et al., 1986) TIPS 8: 24-28. Various studies have now demonstrated that histamine H.sub.3 receptors are found on the histaminergic nerve terminals in the brains of several species, including man (Arrang et al., 1983) Nature 302: 832-837. The H.sub.3 receptor found on the histaminergic nerve terminal was defined as an autoreceptor and could intimately control the amount of histamine released from the neurons. Histamine, the natural compound, was capable of stimulating this autoreceptor but when tested against known H.sub.1 and H.sub.2 receptor agonists and antagonists, a distinct pharmacological profile emerged. Further H.sub.3 receptors have been identified on cholinergic, serotoninergic and monoamine nerve terminals in the peripheral nervous system (PNS) and central nervous system including the cerebral cortex and cerebral vessels. These observations suggest that H.sub.3 receptors are uniquely located to modulate histamine as well as other neurotransmitter release, and H.sub.3 antagonists could be important mediators of neuronal activity.
As stated, CNS histaminergic cell bodies are found in the magnocellular nuclei of the hypothalamic mammillary region and these neurons project diffusely to large areas of the forebrain. The presence of histaminergic cell bodies in the tuberomammillary nucleus of the posterior hypothalamus, a brain area involved in the maintenance of wakefulness, and their projections to the cerebral cortex suggest a role in modulating the arousal state or sleep-wake. The histaminergic projection to many limbic structures such as the hippocampal formation and the amygdaloid complex suggest roles in functions such as autonomic regulation, control of emotions and motivated behaviors, and memory processes.
The concept that histamine is important for the state of arousal, as suggested by the location of histaminergic pathways, is supported by other types of evidence. Lesions of the posterior hypothalamus is well known to produce sleep. Neurochemical and electrophysiological studies have also indicated that the activity of histaminergic neurons is maximal during periods of wakefulness and is suppressed by barbiturates and other hypnotics. Intraventricular histamine induces the appearances of an arousal EEG pattern in rabbits and increased spontaneous locomotor activity, grooming and exploratory behavior in both saline and pentobarbital-treated rats.
In contrast, a highly selective inhibitor of histidine decarboxylase, the sole enzyme responsible for histamine synthesis, has been shown to impair waking in rats. These data support the hypothesis that histamine may function in modulating behavioral arousal. The role of the H.sub.3 receptor in sleep-waking parameters has been recently demonstrated (Lin et al., 1990) Brain Res. 529: 325-330. Oral administration of RAMHA, an H.sub.3 agonist, caused a significant increase in deep slow wave sleep in the cat. Conversely, thioperamide, an H.sub.3 antagonist, enhanced wakefulness in a dose-dependent fashion. Thioperamide has also been shown to increase wakefulness and decrease slow wave and REM sleep in rats. These findings are consistent with in vivo studies demonstrating that thioperamide caused an increase in synthesis and release of histamine. Together, these data demonstrate that selective H.sub.3 antagonists may be useful in the treatment of arousal states and sleep disorders.
Serotonin, histamine and acetylcholine have all been demonstrated to be diminished in the Alzheimer's (AD) brain. The histamine H.sub.3 receptor has been demonstrated to regulate the release of each of these neurotransmitters. An H.sub.3 receptor antagonist would therefore be expected to increase the release of these neurotransmitters in brain. Since histamine has been demonstrated to be important in arousal and vigilance, H.sub.3 receptor antagonists might enhance arousal and vigilance via increasing levels of neurotransmitter release and improve cognition. Thus, the use of H.sub.3 receptor antagonists in AD, attention deficit hyperactive disorders (ADHD), age-related memory dysfunction and other cognitive disorders would be supported.
H.sub.3 receptor antagonists may be useful in treating several other CNS disorders. It has been suggested that histamine may be involved in the control of sleep/wake states as well as states of arousal and alertness, cerebral circulation, energy metabolism, and hyopthalmic hormone secretion. Recent evidence has indicated the possible use of H.sub.3 antagonists in the treatment of epilepsy. Work has demonstrated an inverse correlation between the duration of clonic convulsions and brain histamine levels. Thioperamide, an H.sub.3 antagonist, was also shown to significantly and dose-dependently decrease the durations of every convulsive phase after electrically-induced convulsions and increase the electroconvulsive threshold.
In spite of their low density, H.sub.3 receptor binding sites can be detected outside the brain. Several studies have revealed the presence of H.sub.3 heteroreceptors in the gastrointestinal tract, as well as upon neurons of the respiratory tract. Accordingly, an H.sub.3 receptor antagonist may be useful in the treatment of diseases and conditions such as asthma, rhinitis, airway congestion, inflammation, hyper and hypo motility and acid secretion of the gastrointestinal tract. Peripheral or central blockade of H.sub.3 receptors may also contribute to changes in blood pressure, heart rate and cardiovascular output and could be used in the treatment of cardiovascular diseases.
U.S. Pat. No. 4,707,487 discloses compounds of the general formula: ##STR1## in which R.sub.1 denotes H, CH.sub.3, or C.sub.2 H.sub.5, R denotes H or R.sub.2 and R.sub.2 denotes an alkyl, piperonyl, 3-(1-benzimidazolonyl)-propyl group; a group of formula: ##STR2## in which n is 0, 1, 2, or 3, X is a single bond or alternatively --O--, --S--, --NH--, --CO--, --CH.dbd.CH-- or ##STR3## and R.sub.3 is H, CH.sub.3, F, CN or an acyl group; or alternatively a group of the formula: ##STR4## in which Z denotes an O or S atom or a divalent group NH, N--CH.sub.3, or N--CH, and R.sub.5 denotes an alkyl group, a cycloalkyl group which can bear a phenyl substituent, a phenyl group which can bear a CH.sub.3 of F substituent, a phenylalkyl (C.sub.1 -C.sub.3) group or a naphthyl, adamantyl, or p-toluenesulphonylgroup. It is also disclosed that these compounds antagonize the histamine H.sub.3 receptors and increase the rate of renewal of cerebral histamine.
WO 92/15567 discloses compounds of general formula: ##STR5## wherein: Z is a group of formula (CH.sub.2)m, wherein m=1-5 or a group of the formula: ##STR6## wherein R.sub.6 =(C.sub.1 -C.sub.3) alkyl, R.sub.7 =(C.sub.1 -C.sub.3) alkyl; X represents S, NH, or CH.sub.2 ; R.sub.1 represents hydrogen, (C.sub.1 -C.sub.3) alkyl-, aryl (C.sub.1 -C.sub.10) alkyl-, wherein aryl may optionally be substituted, aryl, (C.sub.5 -C.sub.7) cycloalkyl, (C.sub.1 -C.sub.10) alkyl-, or a group of the formula: ##STR7## wherein n=1-4 R.sub.8 is aryl, aryl (C.sub.1 -C.sub.10)alkyl-, (C.sub.5 -C.sub.7) cycloalkyl- or (C.sub.5 -C.sub.7) cycloalkyl (C.sub.1 -C.sub.10) alkyl-, and R.sub.9 is hydrogen, (C.sub.1 -C.sub.10) alkyl- or aryl; R.sub.2 and R.sub.5 represents hydrogen, (C.sub.1 -C.sub.3) alkyl-, aryl or arylalkyl-, wherein aryl may optionally be substituted; R.sub.3 represents hydrogen, (C.sub.1 -C.sub.3)) alkyl, aryl, or arylalkyl-, wherein aryl may be substituted; and R.sub.4 represents hydrogen, amino-, nitro-, cyano-, halogen-, (C.sub.1 -C.sub.3) alkyl, aryl, or arylalkyl-, wherein aryl may optionally be substituted; wherein aryl is phenyl, substituted phenyl, naphthyl, substituted naphthyl, pyridyl or substituted pyridyl. These compounds are reported to have agonistic or antagonistic activity on the histamine H.sub.3 receptor.
U.S. Pat. No. 5,217,986 discloses compounds of formula: ##STR8## This compound is reported to be active in an H.sub.3 receptor assay, is reported to be an H.sub.3 antagonist on guinea pig ileum, and accordingly is said to be useful in the treatment of diseases and conditions such as asthma, rhinitis, airway congestion, inflammation, cardiac arrhythmias, hypertension, hyper and hypo motility and acid secretion of the gastrointestinal tract, hypo and hyper-activity of the central nervous system, migraine, and glaucoma.
WO 93/14070 discloses compounds of general formula: ##STR9## Chain A represents a hydrocarbon chain, saturated or unsaturated, of 1-6 carbon atoms in length; X represents --O--, --S--, --NH--, --NHCO--, --NHCONH--, --NH--CS--NH--, --NHCS--, --O--CO--, --CO--O--, --OCONH--, --OCON(alkyl)-, --OCONH--CO--, --CONH--, --CON(alkyl)-, --SO--, --CO--, --CHOH--, --NR--C(.dbd.NR")--NR--, R and R' can be hydrogen or alkyl and R" is hydrogen or cyano, or COY.sub.1, Y.sub.1 is alkoxy radical. Chain B represents an alkyl group --(CH.sub.2).sub.n --, n=0-5 or an alkyl chain of 2-8 carbon atoms interrupted by an oxygen or sulfur atom or a group like --(CH.sub.2).sub.n --O-- or --(CH.sub.2).sub.n --S-- wherein n=1 or 2. Y represents (C.sub.1 -C.sub.8) alkyl, (C.sub.3 -C.sub.6) cycloalkyl, bicycloalkyl, aryl, cycloalkenyl, heterocycle.
U.S. Pat. No. 5,290,790 discloses compounds of the same general structure as 4,707,487: ##STR10## but specifically includes amides wherein R.sub.2 is CO--NR'R" and R"R" are independently selected from the group consisting of (a) hydrogen; (b) phenyl or substituted phenyl; (c) alkyl; (d) cycloalkyl; and (e) alkylcycloalkyl such as cyclohexylmethyl or cyclopentylethyl.
The present invention provides, in its principal aspect, compounds of the general formula: ##STR11## where R.sub.2 is a hydrogen or a methyl or ethyl group; R.sub.3 is a hydrogen or a methyl or ethyl group;
n is 0, 1, 2, 3, 4, 5, or 6; and PA1 R.sub.1 is selected from the group consisting of (a) C.sub.3 to C.sub.8 cycloalkyl; (b) phenyl or substituted phenyl; (c) alkyl; (d) heterocyclic; (e) decahydronapthalene; and (f) octahydroindene; PA1 with the proviso that PA1 R.sub.2 is a hydrogen or a methyl or ethyl group; PA1 R.sub.3 is a hydrogen or a methyl or ethyl group; PA1 n is 0, 1, 2, 3, 4, 5, or 6; and PA1 R.sub.1 is selected from the group consisting of (a) C.sub.3 to C.sub.8 cycloalkyl; (b) phenyl or substituted phenyl; (c) alkyl; (d) heterocyclic; (e) decahydronapthalene; and (f) octahydroindene; PA1 when X is NH.sub.2, NH(CH.sub.3), N(CH.sub.3).sub.2, OH, OCH.sub.3, CH.sub.3, SH, and XCH.sub.3 ; A can be --NHCO--, --N(CH.sub.3)--CO--, --NHCH.sub.2 --, --N(CH.sub.3)--CH.sub.2 --, --CH.dbd.CH--, --COCH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH(OH)CH.sub.2, or --C.tbd.C--; PA1 R.sub.2 is a hydrogen or a methyl or ethyl group; PA1 R.sub.3 is a hydrogen or a methyl or ethyl group; PA1 n is 0, 1, 2, 3, 4, 5, or 6; PA1 R.sub.1 is selected from the group consisting of (a) C.sub.3 to C.sub.8 cycloalkyl; (b) phenyl or substituted phenyl; (c) alkyl; (d) heterocyclic; (e) decahydronapthalene; and (f) octahydroindene; PA1 when R.sub.1 and X taken together denote a 5,6 or 6,6 saturated bicyclic ring structure PA1 X can be NH, O, or S; and PA1 when X is constrained in a 5,6 or 6,6 saturated bicyclic ring structure, for example, when X.dbd.NH, R.sub.1 and X taken together mean an octahydroindole ring structure directly attached to A. PA1 R.sub.2 and R.sub.3 are H; PA1 n is 0, 1, 2 or 3; PA1 R.sub.1 is C.sub.6 cyclohexyl, phenyl or substituted phenyl.
when X is H, A can be --CH.sub.2 CH.sub.2 --, --COCH.sub.2 --, --CONH--, --CON(CH.sub.3)--, --CH.dbd.CH--, --C.tbd.C--, --CH.sub.2 --NH--, --CH.sub.2 --N(CH.sub.3)--, --CH(OC)CH.sub.2 --, --NH--CH.sub.2 --, --N(CH.sub.3)--CH.sub.2 --, --CH.sub.2 O--, --CH.sub.2 S--, or --NHCOO--; PA2 when x is HN.sub.2, NC(CH.sub.3), N(CH.sub.3).sub.2 --, OH, OCH.sub.3 CH.sub.3, SH, or SCH.sub.3 ; A can be --NHCO--, --N(CH.sub.3)--CO--, --NHCH.sub.2 --, --N(CH.sub.3)--CH.sub.2 --, --CH.dbd.CH--, --COCH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH(OH)CH.sub.2 --, or --C.tbd.C--; and PA2 when R.sub.1 and X taken together denote a 5,6 or 6,6 saturated bicyclic ring structure X can be NH, O, or S.
The pharmaceutically acceptable salts, hydrates and individual stereoisomers of compounds of the structural formula (1.0) above, as well as mixtures thereof, are also contemplated as falling within the scope of the present invention.
This invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier in combination with an effective amount of a compound of formula (1.0).
The present invention also provides a method of treating conditions in which antagonism of histamine H.sub.3 receptors may be of therapeutic importance such as allergy, inflammation, cardiovascular disease (i.e., hyper or hypotension), gastrointestinal disorders (acid secretion, motility) and CNS disorders involving attention or cognitive disorders (i.e., Alzheimer's, Attention Deficit Hyperactive Disorder, age-related memory dysfunction, stroke, etc.), psychiatric and motor disorders (i.e., depression, schizophrenia, obsessive-compulsive disorders, tourette's, etc.) and sleep disorders (i.e., narcolepsy, sleep apnea, insomnia, disturbed biological and circadian rhythms, hyper and hyposomnolence, and related sleep disorders), epilepsy, hypothalamic dysfunction (i.e., eating disorders such as obesity, anorexia/bulimia, thermoregulation, hormone release) comprising administering an effective amount of a compound of formula (1.0) to a patient in need of such treatment.